Process for the aminocarbonylation of benzazepines and benzodiazepines

ABSTRACT

A new process for preparing substituted 7-aminocarbonyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepines is disclosed.

This is a 371 of International Application PCT/IB96/01502, filed Dec.27, 1996, which claims benefit from U.S. Provisional Application60/009,531, filed Dec. 29, 1995.

FIELD OF THE INVENTION

This invention relates to processes and intermediates for preparingpharmaceutically active compounds. More, particularly, this inventionrelate to the aminocarbonylation of benzazepines and benzodiazepines.

BACKGROUND OF THE INVENTION

Tetraydro-1-benzazepines and tetrahydro-1,4-benzodiazepines form thecore structure of a variety of pharmaceutically useful compounds. Inparticular, WO 93/00095 (PCT/US92/05463) and WO 94/14776(PCT/US93/12436) disclose 7-aminocarbonyl tetrahydro-1-benzazepines andtetrahydro-1,4-benzodiazepines which are reported, to be inhibitors ofthe fibrinogen and vitronectin receptors and useful as inhibitors ofplatelet aggregation, osteoporosis, angiogenesis and cancer metastasis.

Methods to prepare such compounds typically employ a trisubstitutedphenyl derivative as a starting material. The trisubstituted phenylderivative incorporates two substituents to form the azepine ring, and athird substituent to introduce the 7-carbonyl substituent. Such startingmaterials may be difficult and costly to obtain, and may limit thechemistry which may be employed to form the azepine ring,. Priorprocesses generally introduce the aminocarbonyl group into the moleculevia a 7-carboxyl group which is coupled to an amino group byconventional methods for forming amide bonds. Methods disclosed in WO93/00095 and WO 94/14776 are exemplary.

We have now discovered new useful intermediates and a new process forpreparing certain substituted 7-aminocarbonyl benzazepines andbenzodiazepines. The new process uses a simple disubstituted benzene asa starting material, and also introduces the aminocarbonyl function in asingle palladium catalyzed aminocarbonylation step. This process is moreefficient than prior processes for preparing such compounds andadaptable to large scale synthesis.

Various types of palladium catalyzed reactions with aryl and vinylhalides are known to the art, and the problems attendant to their usewith electron rich systems have been studied. For instance, Ziegler etal., J. Org. Chem. 1978, 43, 2941, report that highly activated arylbromides, such as bromo-anilines, reacted very poorly in palladiumcatalyzed vinylic substitution reactions, but observed that someimprovement was noted when aryl iodides were used, and when thepalladium ligand was an tri-o-tolyl phosphine rather than atriphenylphosphine. Cortese et al., J. Org. Chem. 1978 43, 2952, reporta palladium catalyzed vinylic substitution reaction on an o-iodoaniline.

Valentine et al., J. Org. Chem. 1981, 4614, suggest that theunreactivity of o-bromo-anilines toward carbonylation may be overcome byacetylation of the anilino amine group. Kraus et al., Tet. Lett. 199449, 9189 disclose an alkoxycarbonylation of a7-triflic-tetrahydro-1,4benzodiazpine.

Heck et al., J. Org. Chem. 1974, 39, 3327, report typical conditions foraminocarbonylation reactions on aromatic systems; however, they do notreport conditions for aminocarbonylation of electron-rich systems suchas halo-anilines. Certain o-bromoanilines have been reported to undergoaminocarbonylation in low yield by Mori et al., Heterocycles 1981, 161491, and Perry, Chemtech Feb. 18, 1994 reports the use of iodo-aryl andamino-aryl monomers in a palladium catalyzed carbonylation reaction toprepare aramide polymers.

SUMMARY OF THE INVENTION

It is an object of is invention to provide a new and efficient processfor the preparation of 7-aminocarbontyl benzazepines and benzodiazepinesof formula (I):

as hereinafter defined.

One aspect of this invention is an intermediate compound of formula(II):

as hereinafter defined, wherein R¹⁰ is Br or I.

Another aspect of this invention are processes for preparing a compoundof formula (II), wherein R¹⁰ is I or Br, from a compound of formula(IV):

wherein R² and A¹ are as defined for formula (I).

DETAILED DESCRIPTION

This invention comprises a process for preparing compounds of formula(I):

wherein

A¹ is NR¹ or CHR¹;

R¹ is H, T—C₁₋₆alyl, T—C₁₋₆oxoalkyl, T—C₂₋₆alkenyl, T—C₃₋₄oxoalkenyl,T—C₃₋₄oxoalkynyl, T—C₃₋₄alkynyl, C₃₋₆cycloalkyl, Ar or Het, optionallysubstituted by one or more of halo, —OR′, —CN, —NR′₂, —NO₂, —CF₃,—CO₂R′, —CONR′₂, Ar—C₀₋₆alkyl or Het-C₀₋₆alkyl, wherein T is H,C₃₋₆cycloalkyl, Het or Ar.

R² is CH₂CO₂R³;

R³ is H, C₁₋₆alkyl, C₃₋₇cycloalkyl-C₀₋₄alkyl or Ar—C₀₋₄alkyl;

R⁵ is W—(CR′₂)_(q)—Z—(CHR′)^(m), and

R⁶ is H, C₁₋₆alkyl, Ar—C₀₋₆alkyl, Het-C₀₋₆alkyl, orC₃₋₆cycloalkyl-C₀₋₆alkyl, or

R⁵ and R⁶ together form a five- or six-membered Het ring which issubstituted by W;

W is R⁹R″N—, R′R″NR′N—, R′R″NR′NCO—, R′₂NR′NC(═NR′)—, R′ONR′C(═NR′)—,

R′ is H, C₁₋₆alkyl, C₃₋₇cycloalkyl-C₀₋₄alkyl or Ar—C₀₋₄alkyl;

R″ is R′, —C(O)R′ or —C(O)OR″′;

R″′ is H, C₁₋₆alkyl or Ar—C₀₋₄alkyl;

R⁷ is R′, —CF₃, —SR′, or —OR′;

R⁸ is R′, C(O)R′, CN, NO₂, SO₂R′ or C(O)OR¹⁵;

R⁹ is H, C₁₋₆alkyl, C₃₋₇cycloalkyl-C₀₋₄alkyl, Het-C₀₋₄alkl orAr—C₀₋₄alkyl;

X is N═CR′, C(O) or O;

Y is absent, S or O;

Z is (CH₂)_(t), Het, Ar or C₃₋₇cycloalkyl;

q is 0 to 3;

m is 0 to 2; and

t is 0 to 2;

which process comprises:

reacting a compound of formula (II):

wherein

A¹ and R² are as defined above for formula (I); and

R¹⁰ is Cl, Br, I, FSO₃—, ClSO₃— or CF₃SO₃—;

with a Pd catalyst, carbon monoxide and an amine of the formula (III)

wherein R⁵ and R⁶ are defined as above in formula (I) except that anybasic nitrogen group in R⁵ or R⁶ is protected, and thereafter removingany protecting groups.

Suitably R¹ is H, C₁₋₆alkyl or Ar—C₁₋₄alkyl. Preferably R¹ is H. methyl,ethyl, i-propyl, benzyl or phenylethyl. Most preferably R¹ is methyl.

Suitably R³ is C₁₋₆alkyl, Ar or Ar—C₁₋₄alkyl. Preferably R³ is methyl,t-butyl or benzyl.

Preferably, R¹⁰ is Br or I.

Typically the process is carried out by combining the compound offormula (II) with the palladium catalyst, the amine of formula (III) anda base in a suitable solvent and heating the reactants under anAtmosphere of carbon monoxide.

Any stable palladium(0) or palladium(II) source is a suitable catalystfor the aminocarbonylation. (Ph₃P)₄Pd, bis(dibenzylideneacetone)Pd(0),bis(di-(1,2-diphenylphosphino)ethane)Pd(O), PdCl₂, Pd(OAc)₂,(Ph₃P)₂PdCl₂ or (Ph₃P)₂Pd(OAc)₂ are typical.

However, tetrahydro-benzazepine/benzodiazepines in which a bromide ispara to an azepine —NH— are electron rich and, like p-bromo anilines,react poorly in aminocarbonylation reactions under the normal conditionsreported for such reactions. It has now been discovered that catalystloading and the addition of a suitable ligand for the palladium areimportant parameters in such reactions. For instance, at a catalystloading of about 20 mole % of (Ph₃P)₄Pd and 25 mole % of triphenylphosphine, the aminocarbonylation reaction is complete after 5-6 h;whereas, at a catalyst loading of 5 mole % the reaction does not proceedat all. A loading of about 15-100 mole % is suitable, typically about20-25 mole % produces optimal results. Triphenyl phosphine is apreferred ligand for use in the reaction, as it stabilizes andsolubilizes the palladium(0) and provides an active complex. Otherligands may be used, but they generally provide either too muchstabilization so that the complex is inert, or do not provide enoughstabilization so that the metal precipitates.

In spite of the advances realized by the combined use of high catalystloadings and added Pd ligand, the cost of the palladium required for thehigh loading is a serious drawback to the use of such conditions for anindustrial process. Thus, in another aspect, this invention is also animprovement which comprises conducting the reaction in the presence of asmall amount of a reducing agent. Thus, if the reaction is run in thepresence of a suitable reducing agent, such as ammonium formate,cyclohexadiene. hydroquinone, sodium iodide, sodium borohydride orhydrazine hydrate much lower catalyst loadings may be used. Typically,the amount of reducing agent is greater than about 15 mole %, with about20-25 mole % being especially suitable. The reducing agent is believedto facilitate the conversion of the palladium present in the reaction toPd(0). Thus, with the addition of added reducing agent and addedtriphenyl phosphine, catalyst loadings in the range of about 0.5-5% aretypical, with about 2% being fairly suitable. These conditions alsopermit the use of much cheaper sources of palladium in the reaction,such as (Ph₃P)₂Pd(OAc)₂ and (Ph₃P)₂Pd(Cl)₂. Pd(OAc)₂ is a preferredcatalyst.

It has been further found that the use of an iodide as the activatedaryl species greatly facilitates the aminocarbonylation reaction. Thus,when the iodide is used. neither an added palladium ligand, nor areducing agent, nor excessive catalyst loading is required to achieveacceptable results. (Ph₃P)₂Pd(Cl)₂ is a preferred catalyst for the aryliodide.

The reaction may be run in any solvent which is unreactive with thereactants, but a solvent which is able to solvate the palladium speciesis preferred. Toluene, DMF, acetonitrile and dimethylacetamide aresuitable, but N-methylpyrrolidinone is preferred.

Suitably, the temperature of the aminocarbonylation reaction is about70-130° C. Preferably the reaction is run around 90-115° C., morepreferably around 100° C.

The aminocarbonylation reaction may be run without high pressures ofcarbon monoxide. About one atomosphere is typical and preferred. Carbonmonoxide may also be bubbled through the reaction mixture to saturatethe solution.

Typically a base will be included in the reaction mixture to liberatethe amine component (III) if it is used as a salt. In addition, the basemay be used to consume the acid H—R¹⁰ which may be produced during thereaction. Tertiary amines are most suitable for this purpose, such attributylamine, tetramethylethylenediamine and Hunigs base. Hunigs base,diisopropylethylamine, is especially suitable.

The amine component (III) is generally a basic primary or secondaryamine, wherein any other reactive basic centers are protected by anamino protecting group. Protecting groups for such reactive centers, andmethods to remove such protecting groups, are well known in the art andare disclosed for instance by Greene et al., PROTECIVE GROUPS IN ORGANICSYNTHESIS, Second Edition, John Wiley & Sons, New York, 1991. Optionallysubstituted benzyloxycarbonyl, alkyloxycarbonyl, acetyl or benzoylgroups are exemplary. Amino, guanidino and amidino groups are examplesof other reactive centers in the amine component which would beprotected. The butyloxycarbonyl and benzyloxycarbonyl groups arepreferred protecting groups. It will be appreciated, however, that whena symmetric amino component, such as 4,4′-bipiperidine, is used, it maybe unnecessary to protect the second basic center. The protecting groupsare subsequently removed by methods well known in the art, such as bytreatment with acid, for instance trifluoroacetic acid or hydrochloricacid, or by hydrogenation over a palladium or platinum catalyst.

Representative amines of formula (III) are:

wherein E is N or CR′, R^(p) is H or an amino protecting group, such asbenzyloxycarbonyl, t-butyloxycarbonyl or acetyl, n and p are 0-3, andR²⁰ is hydrogen, amino, mono or di-C₁₋₄alkylamino, hydroxy or C₁₋₄alkyl.Preferably n is 2 and p is 1. N′-Benzyloxy-4,4′-bipiperidine andN′-t-butyloxycarbonyl-4,4′-bipiperidine are especially suitable amines.

In a particular embodiment W is or

R^(a) is H, C₁₋₆alkyl, Ar—C₀₋₆alkyl, Het-C₀₋₆alkyl, orC₃₋₆cycloalkyl-C₀₋₆alkyl, halogen, C₁₆alkyl, OR¹, SR¹, COR¹, OH, NO₂,N(R¹)₂, CO(NR¹)₂, CH₂N (R¹)₂;

R^(b) and R^(c) are independently selected from H, C₁₋₆alkyl,Ar—C₀₋₆alkyl, Het-C₀₋₆alkyl, or C₃₋₆cycloalkyl-C₀₋₆alkyl, halogen,C₁₋₆alkyl, OR¹, SR¹, COR¹, OH, NO₂, N(R¹)₂, CO(NR¹)₂, CH₂N(R¹)₂, orR_(b) and R_(c) are joined together to form a five or six memberedaromatic or non-aromatic ring, optionally substituted by halogen,C₁₋₄alkyl, OR¹, SR¹, COR¹, OH, NO₂, N(R¹)₂, CO(NR¹)₂, CH₂N(R¹)₂;

Q is NR′, O or S;

R′ is H, C₁₋₆alkyl, C₃₋₇cycloalkyl-C₀₋₄alkyl or Ar—C₀₋₄alkyl.

In another particular embodiment, W is a six-membered nitrogenheterocycle, such as piperidinyl.

In a specific embodiment, this invention is a method for preparing7-bipiperidin-1-yl]carbonyl]-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepineacetic acid, comprising reacting7-iodo-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine acetic acid, or anester thereof, with an optionally 1′-protected 4-4′-bipiperidine, carbonmonoxide and a palladium catalyst, and thereafter removing anyprotecting groups.

It will also be appreciated that the process of this invention may beused to aminocarbonylate an anilino precursor of thetetrahydro-1-benzazepine and tetrahydro-1,4-benzodiazepines of thisinvention prior to formation of the azepine ring.

The reactive tetrahydro-1-benzazepine or tetrahydro-1,4-benzodiazepineintermediate (II) which is used in the aminocarbonylation reaction maybe prepared by methods analogous to those described in WO 94/14776starting with a suitably trisubstituted halo-phenyl or hydroxy-phenylcompound. The carboxyl function of such intermediates is usually inprotected form. Esters are typical protecting groups for the carboxylfunction of the compounds of formula (II), especially methyl, ethyl,cyclohexyl, phenyl and benzyl esters. These are may be removed byconventional procedures, such as by hydrolysis with a base, for instancean alkali hydroxide or carbonate, or by hydrogenation over a palladiumor platinum catalyst.

In yet another aspect, this invention is a process for preparing theintermediate compound of formula (II), as defined above, wherein R¹⁰ isBr, which comprises reacting a compound of formula (IV):

wherein A¹, A² and R² are as defined in formula (I),

with N-bromosuccinimide and a tetraakyl ammonium halide.Tetrabutylammonium bromide is especially suitable. Although themechanism is not known, the use of the tetraalkyl ammonium halidepromotes bromination para to the anilino nitrogen with a reduced amountof the di-halogenated product. This process is more economical thanbromination with tetrabutyl ammonium tribromide, which is a costlyreagent, and it also avoids the di-halogenation realized when NBS isused alone. 7,9-Dibromination occurs at about 15% when NBS is usedalone; whereas, use of the tetrabutylammonium bromide reduces theproduction of this by product to less than 1%.

In accordance with the above process, a useful intermediate compound ofthis invention is given by formula (IV):

wherein A¹, A² and R² are as defined in formula (I).

In another aspect, this invention is method for preparing theintermediate compound of formula (II), as defined above, wherein R¹⁰ isI, which comprises reacting a compound of formula (IV):

wherein A¹ and R² are as defined in formula (I),

with the ICl.pyridine complex. Iodination of tetrahydro-1-benzazepinesand tetrahydro-1,4benzodiazepines is difficult to accomplish because thenitrogen in the 1-position tends to undergo oxidation under theconditions necessary for iodination giving a double bond at C2 in theazepine ring. It has been discovered that a suitable reagent foraccomplishing this transformation is the ICl.pyridine complex. In fact,this reagent is the only source of I⁺ that does not produce appreciableoxidation of the tetrahydro-1-benzazepine/tetrahydro-1,4-benzodiazepineto yield the corresponding dihydro azepine/diazepine.

In a preferred embodiment, the iodination reaction is carried out in amethanol/methylene dichloride or a water/methylene chloride solventmixture. Using this co-solvent mixture conversions on the order of 95%are realized, whereas, if the reaction is conducted using only methylenedichloride as the solvent the reaction stops at 75-80% conversion.

The meaning of any substituent at any one occurrence in formulas(I)-(IV) or any subformula thereof is independent of its meaning, or anyother substituent's meaning, at any other occurrence, unless specifiedotherwise.

Abbreviations and symbols commonly used in the chemical arts are usedherein to describe the compounds, reactions and reagents of thisinvention. All “loadings” expressed herein, such as catalyst loading,are expressed as a mole % of the aromatic halide or triflate.

C₁₋₄alkyl as applied herein is meant to include methyl, ethyl, n-propyl,isopropyl, n-butyl isobutyl and t-butyl. C₁₋₆alkyl additionally includespentyl, n-pentyl, isopentyl, neopentyl and hexyl and the simplealiphatic isomers thereof. Any C₁₋₄alkyl or C₁₋₆alkyl group may beoptionally substituted by halo, —OR, SR′, —CN, —NR′R′, —NO₂, —CF₃,CF₃S(O)_(r)—, CO_(R)′, —CONR′₂, C₃₋₆cycloalkyl, Het or Ar, unlessotherwise indicated. C₀₋₄alkl and C₀₋₆alkyl additionally indicates thatno alkyl group need be present (e.g., that a covalent bond is present).

C₂₋₆ alkenyl as applied herein means an alkyl group of 2 to 6 carbonswherein a carboncarbon single bond is replaced by a carbon-carbon doublebond. C₂₋₆alkenyl includes ethylene, 1-propene, 2-propene, 1-butene,2-butene, isobutene and the several isomeric pentenes and hexenes. Bothcis and trans isomers are included. Any sp³ carbon atom in theC₂₋₆alkenyl group may be optionally substituted by halo, —OR′, SR′, —CN,—NR′R′, —NO₂, —CF₃, CF₃S(O)_(r)—, —CO₂R′, —CONR′₂, C₃₋₆cycloalkyl, Hetor Ar.

C₃₋₆ alkynyl means an alkyl group of 3 to 6 carbons wherein onecarbon-carbon single bond is replaced by a carbon-carbon triple bond.C₃₋₆ alkynyl includes acetylene, 1-propyne, 2-propyne, 1-butyne,2-butyne, 3-butyne and the simple isomers of pentyne and hexyne. Any sp³carbon atom in the C₃₋₆alkynyl group may be optionally substituted byhalo, —OR′, SR′, —CN, —NR′R′, —NO₂, —CF₃, CF₃S(O)_(r)—, —CO₂R′, —CONR′₂,C₃₋₆cycloalkyl, Het or Ar.

C₁₋₄oxoalkyl refers to an alkyl group of up to four carbons wherein aCH₂ group is replaced by a C(O), or carbonyl, group. Substituted formyl,acetyl, 1-propanal, 2-propanone, 3-propanal, 2-butanone, 3-butanone, 1-and 4-butanal groups are representative. C₁₋₆oxoalkyl includesadditionally the higher analogues and isomers of five and six carbonssubstituted by a carbonyl group. C₃₋₆oxoalkenyl and C₃₋₆oxoalkynylrefers to a C₃₋₆alkenyl or C₃₋₆alkynyl group wherein a CH₂ group isreplaced by C(O) group. C₃₋₄oxoalkenyl includes 1-oxo-2-propenyl,3-oxo-1-propenyl, 2-oxo-3-butenyl and the like.

A substituent on a C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl or C₁₋₆oxoalkyl group, may be on any carbon atom which results in a stablestructure, and is available by conventional synthetic techniques.

T—C₁₋₆ alkyl refers to a C₁₋₆ alkyl group wherein in any position acarbon-hydrogen bond is replaced by a carbon-T bond. T—C₂₋₆ alkenyl andT—C₃₋₆ alkynyl have a similar meaning with respect to C₂₋₆ alkenyl andC₃₋₆ alkynyl.

Ar, or aryl, as applied herein, means phenyl or naphthyl, or phenyl ornaphthyl substituted by one to three moieties. In particular, suchmoieties may be C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkylthio, trifluoromethyl,OH, F, Cl, Br or I.

Het, or heterocycle, indicates an optionally substituted five or sixmembered monocyclic ring, or a nine or ten-membered bicyclic ringcontaining one to three heteroatoms chosen from the group of nitrogen,oxygen and sulfur, which are stable and available by conventionalchemical synthesis. Illustrative heterocycles are benzofuran,benzimidazole, benzopyran, benzothiophene, furan, imidazole, indoline,morpholine, piperidine, piperazine, pyrrole, pyrrolidine,tetrahydropyridine, pyridine, thiazole, thiophene, quinoline,isoquinoline, and tetra- and perhydro-quinoline and isoquinoline. A sixmembered ring heterocycle containing one or two nitrogens, such aspiperidine, piperazine, tetrahydropyridine and pyridine, are preferredheterocycles. Piperidine is a preferred Het for the moiety Z.

C₃₋₇cycloalkyl refers to an optionally substituted carbocyclic system ofthree to seven carbon atoms, which may contain up to two unsaturatedcarbon-carbon bonds. Typical of C₃₋₇cycloalkyl are cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl andcycloheptyl. Any combination of up to three substituents, such as chosenfrom C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkylthio, trifluoromethyl, OH, F, Cl,Br or I, on the cycloalkyl ring that is available by conventionalchemical synthesis and is stable, is within the scope of this invention.

{circle around (N)} as used herein indicates a nitrogen heterocycle,which may be a saturated. or unsaturated stable five-, six- orseven-membered monocyclic ring, or a seven- to ten-membered bicyclicring containing up to three nitrogen atoms or containing one nitrogenatom and a heteroatom chosen from oxygen and sulfur, and which may besubstituted on any atom that results in a stable structure. The nitrogenatom in such ring may be substituted so as to result in a quaternarynitrogen. The nitrogen heterocycle may be substituted in any stableposition by R²⁰, for instance H, C₁₋₄alkoxy, F, Cl, Br, I, NO₂, NR′₂,OH, CO₂R′, CONHR′, CF₃, T—C₀₋₄alkyl, T—C₁₋₄alkyl-S(O)_(u) (e.g., where uis 0, 1 or 2) or C₁₋₄alkyl substituted by any of the aforementionedsustituents. Representative of {circle around (N)} are pyrroline,pyrrolidine, imidazole, benzimidazole, aza-benzimidazole, imidazoline,imidazolidine, pyrazole, pyrazoline, pyrazolidine, piperidine,piperazine, morpholine, pyridine, pyridinium, tetrahydropyridine,tetrahydro- and hexahydro-azepine, quinuclidine, quinuclidinium,quinoline, isoquinoline, and tetra- and perhydro-quinoline andisoquinoline. In particular, {circle around (N)} may be pyridyl,pyrolidinyl, piperidinyl, piperazinyl, azetidinyl, quinuclidinyl ortetrahydropyridinyl. {circle around (N)} is preferably 2 or 4-pyridyl,2-(6-amino-pyridyl), 4-(2-amino-pyridyl), 4-tetrahydropyridyl,4-piperidinyl or 4-piperazinyl.

When {circle around (N)} is a heterocycle of the formula

R^(b) and R^(c) are joined together to form a five- or six-memberedaromatic or non-aromatic ring. The ring formed will generally be a five-or six-membered heterocycle selected from those listed above for Het, orwill be a phenyl, cyclohexyl or cyclopentyl ring. Phenyl, 2,3-pyridyl(e.g., where the five-membered ring is formed between the 2 and 3positions of a pylidyl ring), 3,4-pyridyl, 4,5 pyridyl and4,5-pyrimidyl, each optionally substituted by C₁₋₄alkyl are preferredmoieties for such a ring.

Certain radical groups are abbreviated herein. t-Bu refers to thetertiary butyl radical, Boc refers to the t-butyloxycarbonyl radical,Fmoc refers to the fluorenylmethoxycarbonyl radical, Ph refers to thephenyl radical, Cbz refers to the benzyloxycarbonyl radical, Bn refersto the benzyl radical, Me refers to methyl, Et refers to ethyl, Acrefers to acetyl, Alk refers to C₁₋₄alkyl, Nph refers to 1- or2-naphthyl and cHex refers to cyclohexyl.

Certain reagents are abbreviated herein. DCC refers todicyclohexylcarbodiimide, DMAP refers to dimethylaminopyridine, DIEArefers to diisopropyletlylunine, THF refers to tetrahydrofuran, DMFrefers to dimethyl formamide, NBS refers to N-bromosuccinimide, Pd/Crefers to a palladium on carbon catalyst, TEA refers to triethylamine,TFA refers to trifluoroacetic acid.

If the amine component of the amide bond-forming reaction contains aprotecting group, the protecting group can be removed either prior orsubsequent to the ester hydrolysis step, using methods suitable forselective deprotection of the specific protecting group employed. Suchmethods are described in Green, “Protective Groups in Organic Synthesis”(published by Wiley-Interscience). For example, if the amine componentcontains a nitrogen group which is protected by a tert-butoxycarbonyl(BOC) group, the BOC group is removed under acidic conditions, using,for instance, HCl in dioxane or trifluoroacetic acid (TFA) in CH₂Cl₂.

The simple starting materials for preparing the compounds of thisinvention are commercially available or prepared by routine methods wellknown in the art.

The intermediate compounds of this invention are useful as intermediatesin the preparation of pharmaceutically active compounds, in particularcompounds which have fibrinogen and vitronectin antagonist properties.

General

Nuclear magnetic resonance spectra were recorded at either 250 or 400MHz using, respectively, a Bruker AM 250 or Bruker AC 400 spectrometer.CDCl₃ is deuteriochloroform, DMSO-d₆ is hexadeuteriodimethylsulfoxide,and CD₃OD is tetradeuteriomethanol. Chemical shifts are reported in parmper million (δ) downfield from the internal standard tetramethylsilane.Abbreviations for NMR data are as follows: s=singlet, d=doublet,t=triplet, q=quartet, m=multiplet, dd=doublet of doublets, dt=doublet oftriplets, app=apparent, br=broad. J indicates the NMR coupling constantmeasured in Hertz. Continuous wave infrared (IR) spectra were recordedon a Perkin-Elmer 683 infrared spectrometer, and Fourier transforminfrared (FTIR spectra were recorded on a Nicolet Impact 400 D infraredspectrometer. IR and FIIR spectra were recorded in transmission mode,and band positions are reported in inverse wavenumbers (cm⁻¹). Massspectra were taken on either VG 70 FE, PE Syx API III, or VG ZAB HFinstruments, using fast atom bombardment (FAB) or electrospray (ES)ionization techniques. Elemental analyses were obtained using aPerkin-Elmer 240C elemental analyzer. Melting points were taken on aThomas-Hoover melting point apparatus and are uncorrected. Alltemperatures are reported in degrees Celsius.

Analtach Silica Gel GF and E. Merck Silica Gel 60 F-254 thin layerplates were used for thin layer chromatography. Both flash and gravitychromatography were carried out on E. Merck Kieselgel 60 (230-400 mesh)silica gel. Analytical and preparative HPLC were carried out on Raini orBeckman chromatographs. ODS refers to an octadecylsilyl derivatizedsilica gel chromatographic support. 5μ Apex-ODS indicates anoctadecylsilyl derivatized silica gel chromatographic support having anominal particle size of 5μ, made by Jones Chromatography, Littleton,Colo. YMC ODS-AQ® is an ODS chromatographic support and is a registeredtrademark of YMC Co. Ltd., Kyoto, Japan. PRP-1® is a polymeric(styrene-divinylbenzene) chromatographic support, and is a registeredtrademark of Hamilton Co., Reno, Nev. Celite® is a filter aid composedof acid-washed diatomaceoug silica, and is a registered trademark ofManville Corp., Denver, Colo.

The following procedures illustrate the method of carrying out theinvention.

Preparation of the Tetrahydro-3-oxo-1,4-benzodiazepine Ring System

EXAMPLE 1 Preparation of Methyl(S)-2,3,4,5-tetrahydro-3-oxo-1H-1,4-benzodiazepine-2-acetate

a) Dimethyl (R)-malate O-triflate

A solution of dimethyl (R)-malate (12.96 g, 80 mmol) and pyridine (6.8mL, 84 mmol) in CH₂Cl₂ (50 mL) was added dropwise under argon at 0° to asolution of triflic anhydride (14.2 mL, 84 mmol) in dry CH₂Cl₂ (40 mL)in a flame-dried flask. The resulting yellow-orange mixture was stirredat 0° C. for 30 min, and then at RT for 4 h. The reaction was quenchedby adding H₂O (50 mL) and the organic phase was washed three times withH₂O and brine, dried (MgSO₄), and concentrated to give the titlecompound as an off white solid (22.45 g, 95%): MS (ES) m/e 295.0 [M+H]⁺.

b) Dimethyl N-[2-(cyano)phenyl]-(S)-aspartate

A solution of compound of Example 1(a) (22.4 g, 76.2 mmol) in 1:1CH₃Cl:hexane (80 mL) was added to a solution of 2-aminobenzonitrile (9.0g, 76.2 mmol) and 2,6-di-tert-butylpyridine (14.5 g, 76.2 mmol) in 1:1CH₃Cl-hexane (100 mL) in a flame-dried flask under argon at 0° C. Theresulting mixture was stirred at 0° C. for 30 min and then at RT for 3d. The resulting mixture was concentrated, the residue was taken up intoEtOAc, washed with 5% HCl and brine, and dried (MgSO₄). The resultingmixture was concentrated and the residue was purified by flashchromatography (silica gel, 12% EtOAc/hexane) to give the title compoundas a clear oil (12.3g, 62%): MS (ES) m/e 263.3 [M+H]⁺.

c) Methyl (S)-2,3,4,5-Tetrahydro-3-oxo-1H-1,4-benzodiazepine-2-acetate

A mixture of compound of Example 1(b)(12 g, 45.7 mmol), Et₃N (7.64 mL,54.84 mmol), and Raney-Ni (46 g, prewashed by CH₃OH) in CH₃OH (200 mL)was stirred at RT under a H₂ balloon for 2 d. The mixture was filteredand the catalyst was washed 3× with CH₃OH. The filtrate was concentratedand the residue was purified by flash chromatography (silica gel stepgradient, 0-5% CH₃OH/CH₂Cl₂) to yield the title compound as a whitesolid (7.93 g, 74%): MS (ES) m/e 235.3 [M+H]⁺. The title compound wasshown to contain approximately 23% of the (R)-enantiomer by NMR.

Bromination of the tetrahydro-3-oxo-1,4-benzodiazepine

EXAMPLE 2 Preparation of Methyl2,3,4,5-tetrahydro-7-bromo-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetate

Methyl 2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetate(100 g, 0.4 mole) and n-Bu₄ N Br (13 g, 0.04 mole) were added to CH₂Cl₂(1.0 liter) and refluxed for 0.5 hr. The reaction mixture was cooled to28° C. and N-Bromosuccinimide added in small portions (72.8 g, 0.41mole). The reaction was stirred at ambient temperature for 1.0 hr thenwashed with 5% NaHCO₃ solution (400 ml) then water (2×400 ml) CH₂Cl₂(800 ml) was replaced with hexane (800 ml) via ‘put and take’distillation, the resulting slurry was cooled, filtered and washed withhexane. The product was dried in vacuo to yield the title compound (123g, 93%). HPLC analysis showed 0.7% residual starting material and 0.7%7,9-dibromide.

Iodination of the tetrahydro-3-oxo-1,4-benzodiazepine

EXAMPLE 3 Preparation of Methyl(S)-2,3,4,5-tetrahydro-7-iodo-3-oxo-1H-1,4-benzodiazepine-2-acetate

Pyridine-ICl complex: 1M iodinemonochloride in CH₂Cl₂ (100 mL) was addedslowly to a solution of pyridine (8.5 mL, 105 mmol) in CH₂Cl₂ (20 mL),stirred under argon and pre-cooled to 50° C., so as to maintain aninternal temperature between 10-15° C. The mixture was stirred at 5-10°C. for 20 min. Hexane (50 mL) was added and the mixture was stirred in acold bath for an additional 30 min. The solid which formed was collectedby filtration, washed with hexane and with petroleum ether, and dried toyield pyridine-ICl complex (22.5 g) as a yellow solid which was usedwithout further purification.

Pyridine-ICl complex (1.27 g, 5.28 mmol) was added portionwise to asolution of the methyl(S)-2,3,4,5-tetrahydro-1-oxo-1H-1,4-benzodinapine-2-acetate (1.18 g, 4.8mmol) in 1:1 CH₂Cl₂: CH₃OH (40 mL). The resulting mixture was stirred atRT for 40 min, treated with 1M NaHSO₃ (20 mL), and the resulting solidwas collected by filtration, washed with Et₂O, and dried to yield thetitle compound as an off white solid (1.72 g, quantitative): MS (ES) m/e361.2 [M+H]⁺.

EXAMPLE 4 Preparation of Methyl2,3,4,5-tetrahydro-7-iodo-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetate

Methyl 2,3,4,5-tetrahydro-3-oxo-4-methyl-1H-1,4-benzodiazepine-2-acetate(80 g, 0.32 mole) was added to CH₂Cl₂ (400 ml) and MeOH (400 ml). Themixture was heated at 40° C. for 0.5 hr then cooled to 25° C. Pyridineiodine monochloride complex was added in portions (82g, 0.51 mole).After the addition, the reaction was stirred for 10 minutes then CH₂Cl₂(400 ml) added. The reaction mixture was stirred for 1.0 hr then washedwith sodium metabisulphite solution (5 g+400 ml water), followed bywater (400 ml). The temperature was maintained at 30° C. during thewashing process. CH₂Cl₂ (450 ml) was replaced with 60/80 petrol (450 mlby ‘put and take’ distillation. A further portion of CH₂Cl₂ (200 ml) wasreplaced with 60/80 petrol, the mixture cooled slowly to 10° C., and theproduct filtered off and washed with 60/80 petrol. The product was driedin vacuo to yield the title compound (108 g, 92%).

EXAMPLE 5 Preparation of Methyl2,3,4,5-tetrahydro-7-iodo-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetate

Methyl 2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetate(100 g, 0.4 moles) was added to CH₂Cl₂ (500 ml) plus MeOH (500 ml) andheated at 40° C. for 0.5 hr. The solution was cooled to 26° C. andpyridine (64 g, 0.8 mole) added. Iodine monochloride (71.3 g, 0.44 mole)dissolved in CH₂Cl₂ (500 ml) was added dropwise over 30 minutes and thereaction stirred for a further 1.0 hr. The product was filtered off,washed with 60/80 petrol and dried in vacuo to yield the title compound(113 g, 75%).

Aminocarbonylation of tetrahydro-3-oxo-1,4-benzodiazepines

EXAMPLE 6 Preparation of2,3,4,5-Tetrahydro-7-[[(N′-benzyloxycarbonyl)-4,4′-bipiperidinyl]carbonyl]-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-aceticacid

a) methyl (R,S)7-(4,4′-bipiperidin-1-yl)-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetate

Methyl2,3,4,5-tetrahydro-7-bromo-4-methyl-3-oxo-1H-1,4benzodiazepine-2-acetate(5 g, 0.015 mole), Hunigs base, (18.2 g, 0.14 mole), Ph₃P (0.31 g,0.0031 mole), Pd(OAc)₂ (0.07 g,0.00031 mole) andN-Cbz-4,4′-bipiperidine-HCl salt (7.3 g, 0.021 mole) were dissolved inN-methylpyrrolidinone (40 ml). The reaction mixture was heated to 110°C. whilst bubbling carbon monoxide through the solution. The temperaturewas maintained at 110° C. keeping the reaction under 1 atmosphere ofcarbon monoxide. Ammonium formate solution (0.5 ml of 0.6 g in 5 mlwater) was added each hour, total reaction time 4 hours (2.0 ml added).

Excess Hunigs base was the distilled off under vacuum and the residuecooled and diluted with CH₂Cl₂ (30 ml). This was washed with water (2×30ml). Tne CH₂Cl₂ was removed under vacuum and the residue dissolved inEtOAc (80 ml). The solution was stirred for three days then filtered andwashed with cold EtOAc (6.52 g, 74%).

b) methyl (R,S)7-(4,4′-bipiperidin-1-yl)-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetate

A solution of the compound of Example 6(a) (0.06 mmol) in methanol (25mL) containing 1.0M hydrogen chloride in ether (0.6 mL) was treated with10% palladium hydroxide and the mixture was shaken in a hydrogenatmosphere (40 psi) for 1 h. The mixture was filtered and concentratedto yield the title compound.

c) (R,S)7-(4,4′-bipiperidin-1-yl)-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-aceticacid

The compound of Example 6(b) (0.26 mmol) is dissolved in methanol (9mL), and 1.0 N sodium hydroxide (0.81 mL, 0.81 mmol) was added. Thesolution was stirred at RT overnight, and concentrated. The residue wasdissolved in waterlacetonitrile (3 mL), cooled to 0° C., acidified withHCl, and concentrated to yield the title compound.

EXAMPLE 7 Preparation of(S)-2,3,4,5-Tetrahydro-7-[[[benzimidazol-2-yl)methyl]methylamino]carbonyl]-3-oxo-1H-1,4-benzodiazepine-2-aceticacid

a) Methyl(S)-2,3,4,5-tetrahydro-7-[[N-[(benzimidazol-2-yl)methyl]-N-methylamino]carbonyl]-3-oxo-1H-1,4-benzodiazepine-2-acetate

A mixture of methyl(S)-2,3,4,5-tetrahydro-7-bromo-3-oxo-1H-1,4-benzodiazepine-2-acetate(1.5 g, 4.77905 mmol), 2-(methylaminoinethyl)benzimidazoledihydrochloride (2.24 g, 9.5809 mmol), triphenylphosphine (1.26 g,4.7905 mmol), n-Bu₃N (6.21 g, 33.5333 mmol), and (Ph₃P)₄Pd (1.10 g,0.9581 mmol) in N-methyl 2-pyrrolidinone (20 mL) was flushed with argonand carbon monoxide for 10 min. The mixture was then heated at 100-105°C. under a carbon monoxide balloon for 8 hr. The mixture was cooled andacidified with 6 N HCl to pH=2. The solution was extracted with EtOAc,and the EtOAc layer was discarded. The aqueous layer was neutralizedwith 30% NaOH and extracted with CH₂Cl₂. The organic extracts were driedover MgSO₄, concentrated, and purified by silica gel flash columnchromatography (5% MeOH/CH₂Cl₂) to give the title compound (1.62 g, 80%)as an off white solid: ¹H NMR (250 MHz, DMSO-d₆): δ2.65 (dd, J=16.3, 7.6Hz, 1H), 2.81 (dd, J=16.3, 5.9 Hz, 1H), 3.05 (s, 3H), 3.60(s, 3H), 3.75(dd, J=16.3, 6.9 Hz, 1H), 4.78 (s, 2H), 4.95 (m, 1H), 5.05 (dd, J=16,5.3 Hz, 1H), 6.20 (d, J=5.9 Hz, 1H), 6.55 (d, J=7.6 Hz, 1H), 7.25 (m,4H), 7.55 (m, 2H), 8.21 (t, J=5.3 Hz, 1H).

b) (S)-2,3,4,5-Tetrahydro-7-[[[benzimidazol-2-yl)methyl]methylaminocarbonyl]-3-oxo-1H-1,4-benzodiazepine-2-acetic acid

Following the procedure of Example 7(a), methyl(S)-2,3,4,5-tetrahydro-7-[[N-[(benzimidazol-2-yl)methyl]-N-methylamino]carbonyl]-3-oxo-1H-1,4-benzodiazepine-2-acetatewas saponified to afford the title compound (0.060 g, 57%) as an offwhite solid: ¹H NMR (400 MHz, DMSO-d₆) δ2.52 (dd,J=16.3, 7.6 Hz, 1H),2.84 (dd, J=16.3, 5.9 Hz, 1 Hz, 3.20 (s, 3H), 3.75 (dd, J=16.3, 6.9 Hz,1H), 4.95 (t, J=5.9 Hz, 1H), 5.05 (dd, J=16, 5.3 Hz, 1H), 5.10 (s, 2H),6.59 (d, J=7.6 Hz, 1H), 7.12 (s, 1H), 7.20 (d, J=7.6 Hz, 1H), 7.48 (m,2H), 7.69 (m, 2H), 7.90 (d, J=5.3 Hz, 1H); IR (KBr) 3600-3100,3100-2800, 1681, 1613, 1601, 1485, 1445, 1314, 830, 764, 742 cm⁻¹; MS(ES) m/e 422 (M+H)⁺. Anal. Calcd for C₂₁H₂₁N₅O₄: C, 61.91: H, 5.20: N,17.19. Found; C, 61.57; H, 5.32; N, 17.29.

EXAMPLE 8 Preparation of(S)-2,3,4,5-Tetrahydro-7-[[[(4-aza-5-methylbenzimidazol-2-yl)methyl]methylamino]carbonyl]-3-oxo-1H-1,4benzodiazepine-2-aceticacid

a) Methyl(S)-2,3,4,5-tetrabydro-7-[[[(4-aza-5-methylbenzimidazol-2-yl)methyl]methylamino]carbonyl]-3-oxo-1H-1,4-benzodiazepine-2-acetate

A mixture containing methyl(S)-2,3,4,5-tetrahydro-7-bromo-3-oxo-1H-1,4-benzodiazepine-2-acetate(624 mg, 2 mmol), 2-(aminomethyl)4-aza-5-methylbenzimidazoledihydrochloride (695 mg, 2.8 mmol), DIEA (1.8 mL, 10 mmol), and(Ph₃P)₂PdCl₂ (126 mg, 0.18 mmol) in NMP (22 mL) was heated to 110° C.under a CO balloon for 48 hr. The solvent was removed on the rotavap(high vacuum) and the residue was purified by silica gel flashchromatography (0.5-5% CH₃OH/CH₂Cl₂) to give the title compound (170 mg,19.5%) as a pale yellow solid: MS (ES) m/e 437.5 (M+H)⁺.

b)(S)-2,3,4,5-Tetrahydro-7-[[[(4-aza-5-methylbenzimidazol-2-yl)methyl]methylamino]carbonyl]-3-oxo-1H-1,4-benzodiazepine-2-aceticacid

1.0 M LiOH (0.6 mL, 0.6 mmol) was added dropwise to a solution of methyl(S)-2,3,4,5-tetrahydro-7-([[(4-aza-5-methylbenzimidazol-2-yl)methyl]methylamino]carbonyl]-3-oxo-1H-1,4-benzodiazepine-2-acetate(170 mg, 0.39 mmol) in CH₃OH (5 mL) and ThF (5 mL) at RT. The resultingmixture was stirred for 20 hr and then was concentrated. The residue wasdissolved in H₂O, acidified with 30% TFA, and purified by ODSchromatography (5% CH₃CN/H₂O containing 0.1% TFA). Concentration andlyophilization gave the title compound as an off white powder: [α]_(n)²⁵−74.5° (c 1, CH₃OH); MS (ES) m/e 423.2 (M+H)⁺. Anal. Calcd forC₂₁H₂₂N₆O₄.2 TFA.1.75 H₂O: C, 44.03; H, 4.06; N, 12.32. Found: C, 44.33;H, 4.04; N, 12.28.

EXAMPLE 9 Preparation of Methyl2,3,4,5-tetrahydro-7-[[(N′-benzyoxycarbonyl)-4,4′-bipiperidinyl]carbonyl]-3-oxo-4-methyl-1H-1,4-benzodiazepine-2-acetate

N-CBZ-4,4′-bipiperidine-HCl salt (1.18 g, 0.0035 mole) was dissolved inhot N-methylpyrrolidone (8 ml) and filtered. To the filtrate was addedHunigs base (3.64 g, 0.028 mole), methyl2,3,4,5-tetrahydro-7-iodo-3-oxo-1H-1,4-benzodiazepine-2-acetate (1.0 g,0.0027 mole) and (Ph₃P)₂ PdCl₂ (0.038 g, 5.4'10⁻⁶ mole) added. Themixture was degassed and heated at 90-100° C. under one atmosphere ofcarbon monoxide for 2.0 hours. The reaction was cooled and the productisolated in an identical manner to that described for the precedingExample 6 to yield the title compound (1.38 g, 90%).

EXAMPLE 10 Preparation of7-[[(1′-benzyloxycarbonyl)-4,4′-bipiperidinyl]carbonyl]-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-aceticacid

A slurry of 7-iodo-3-oxo-2,3,4,5-tetrahydro-1,4-benzodiazepine-2-aceticacid (7.2 g, 0.02 mol), 1′-benzyloxycarbonyl-4,4′-bipiperidinehydrochloride (0.026 mol), Hunigs base (0.1 mol) anddichlorobis(triphenylphosphine) palladium (II) (2 mol % in 8 volanisole) was stirred and heated to 95° C. while bubbling with nitrogen.The mixture was flushed with carbon monoxide, then heated under anatmosphere of carbon monoxide for approximately 2 hours after whichpalladium black precipitated from solution. Analysis by HPLCdemonstrated that reaction was complete. The reaction mixture was cooledto 80° C. and the product was extracted with water (8 vol) at thistemperature. After separating, the organic phase was washed with morewater (8 vol) and separted. The combined aqueous phases were distilledat atmospheric pressure to remove residual anisole and Hunigs base. Thedistillation was stopped when no more organic material could be seen todistill. The residual aqueous solution was cooled to room temperature,acidified to pH 2 with 10% hydrochloric acid and the productprecipitated from solution as white solid. The product was filteredunder suction, washed with water and dried in vacuum oven at 50° C. toafford the title compound as a dark solid (10.2 g, 91%).

EXAMPLE 11 Preparation of methyl (S)7-[[(N′-benzyloxycarbony)-4,4′-bipi.peridinyl]carbonyl]-3-oxo-2,3,4,5-tetrahydro-1,4-benzodiazepine-2-aceticacid

a) methyl7-[[(N′-benzyloxycarbonyl)-4,4′-bipiperidinyl]carbonyl]-3-oxo-2,3,4,5-tetrahydro-1,4-benzodiazepine-2-acetate

A mixture of methyl7-iodo-3-oxo-2,3,4,5-tetrahydro-1,4-benzodiazepine-2-acetate (50 g, 134mmol), N′-benzyloxycarbonyl-4,4′-bipiperidine hydrochloride (52.12 g,154 mmol), Hunigs base (67.9 ml, 402 mmol.), NMP (200 ml), water (5.2ml, 289 mmol) and palladium II chloride bistriphenylphosphine (1.88 g,2.68 mmol) was shaken in a Parr shaker at 95° C. under carbon monoxideat 8-14 psi. After 4 h carbon monoxide uptake ceased and the reactionmixture was allowed to cool to room temperature. Dichloromethane (400ml) was then added and the solution was filtered and washed with water.The organic layer was concentrated to dryness and the residue wasslurried in methanol (770 ml). The product was filtered and washed withmethanol and sucked dry to afford the title compound (54 g, 70%).

b) (S)7-(4,4′-bipiperidinyl)carbonyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-aceticacid

The compound of Example 11(a) was dissolved in t-butanol and buffer (70ml, pH 7.0, 0.1 N phosphate). Candida antarctica lipase, supported onmacroporous acrylate resin (200 mg, /700 PLU/g, marketed as Novozym 435)was added and the reaction stirred at ambient temperature for 4.0 days.The pH was adjusted to 8.0 with NaOH solution and EtOAc added (75 ml).The mixture was filtered, and the EtOAc layer separated. The aqueouslayer was re-extracted with EtOAc, the combined EtOAc extracts weredried (Na₂SO₄) and the EtOAc evaporated in vacuo to yield the (R)-ester.

The aqueous phase was adjusted to pH 5 with HCl and extracted withEtOAc. The combined EtOAc extracts were dried (Na₂SO₄) and evaporated toleave the (S) acid (99% e.e.)

A solution of the (S) acid (0.15 mmol) in methanol (40 mL) and aceticacid (8 drops) was shaken in a hydrogen atmosphere (45 psi) with 10%Pd/C (20 mg) for 30 min. The mixture was filtered through Celite and thefiltrate concentrated in vacuo to yield the title compound.

EXAMPLE 12 Preparation of(S)-2,3,4,5-Tetrahydro-3-oxo-7-[[[2-[2-(pyridinyl)amino]ethyl]amino]carbonyl]-1H-1,4benzodiazepine-2-aceticacid

a) Methyl(S)-2,3,4,5-Tetrahydro-3-oxo-7-[[[2-[2-(pyridinyl)amino]ethyl]amino]carbonyl]-1H-1,4-benzodiazepine-2-acetate

A mixture of Methyl(S)-2,3,4,5-Tetrahydro-7-iodo-3-oxo-1H-1,4-benzodiazepine-2-acetate (720mg, 2 mmol), N-(2-pyridinyl)ethylenediamine (672 mg, 3 mmol), DIEA (1.8mL, 10 mmol), and (Ph₃P)₂PdCl₂ (140 mg, 0.2 mmol) inN-methyl-2-pyrrolidinone (20 mL) was heated to 110° C. under CO balloonfor 3 h. The mixture was concentrated and the residue was purified byflash chromatography (silica gel, step bradient, 0-7% CH₃OH/CH₂Cl₂) togive the title compound as a pale yellow semisolid: MS (ES) m/e 398.2[M+H]⁺.

b)(S)-2,3,4,5-Tetrahydro-3-oxo-7-[[[2-[2-(pyridinyl)amino]ethyl]amino]carbonyl]-1H-1,4-benzodiazepine-2-aceticacid

1M LiOH (3.8 mL, 3.8 mmol) was added dropwise to a solution of thecompound of Example 12(a) (1 g, 2.5 mmol) in 1:1 CH₃OH:THF (20 mL) atRT. The resulting mixture was stirred for 20 h and concentrated . Theresidue was dissolved in H₂O, acidified with TFA (20%), and purified bychromatography (ODS, 6% CH₃CN/H₂O-0.1% TFA). Fractions containing thedesired product were pooled, concentrated, and lyophilized to give thetitle compound [may contain approximately 23% of the R-enantiomer, seePreparation 6(c)] as a pale yellow powder: MS (ES) m/e 384.2[M+H]⁺.Anal. Calcd for C₁₉H₂₁N₅O₄.2.5 TFA: C,41.87; H, 3.44; N, 10.17. Found:C, 42.01; H, 3.62; N, 10.15.

EXAMPLE 13 Preparation of(S)-2,3,4,5-Tetrahydro-7-[[[(benzimidazol-2-yl)methyl]amino]carbonyl]-3-oxo-1H-1,4-benzodiazepine-2-aceticacid

a) Methyl(S)-2,3,4,5-tetrahydro-7-[[[(benzimidazol-2-yl)methyl]amino]carbonyl]-3-oxo-1H-1,4-benzodiazepine-2-acetate

A mixture of methyl(S)-2,3,4,5-tetrahydro-7-ixdo-3-iodo-1H-1,4-benzodiazepine-2-acetate(1.08 g, 3 mmol), 2-aminomethylbenzimidazole dihydrocnloride hydrate(924 mg, 4.2 mmol), DIEA (2.6 mL, 15 mmol), and (Ph₃P)₂PdCl₂ (211 mg,0.3 mmol) in NMP (30 mL) was heated to 110° C. under a CO balloon for 3hr. The solvent was removed on the rotavap (high vacuum) and the residuewas purified by silica gel flash chromatography (0-7% CH₃OH/CH₂Cl₂) toafford the title compound (530 mg, 44%) as an off white solid: MS(ES)m/e 408.1 (M+H)⁺.

b)(S)-2,3,4,5-Tetrahydro-7-[[[(benzimidazol-2-yl)methyl]amino]carbonyl]-3-oxo-1H-1,4-benzodiazepine-2-aceticacid

Methyl(S)-2,3,4,5-tetrahydro-7-[[[(benzimidazol-2-yl)methyl]amino]carbonyl]-3-oxo-1H-1,4-benzodiazepine-2-acetateis hydrolyzed with 1M LiOH to yield the title compound (66%) as a whitepowder: [α]_(n) ²⁵ −145.3° (c=1, CH₃OH); MS (ES) m/e 394.2 (M+H)⁺. Anal.Calcd for C₂₀H₁₉N₅O₄.2 TFA.0.125 H₂O: C, 46.22; H, 3.43; N, 11.23.Found: C, 46.13; H, 3.78; N, 11.49.

The above description fully discloses how to make and us the presentinvention. However, the present invention is not limited to theparticular embodiments described hereinabove, but includes allmodifications thereof within the scope of the following claims. Thevarious references to journals, patents and other publications which arecited herein comprises the state of the art and are incorporated hereinby reference as though fully set forth.

What is claimed is:
 1. A process for preparing compounds of formula (I):

wherein A¹ is NR¹ or CHR¹; R¹ is H, T—C₁₋₆alkyl, T—C₁₋₆oxoalkyl,T—C₂₋₆alkenyl, T—C₃₋₄oxoalkenyl, T—C₃₋₄oxoalkynyl, T—C₃₋₄alynyl,C₃₋₆cycloalkyl, Ar or Het, optionally subsituted by one or more of halo,—OR′, —CN, —NR′₂, —NO₂, —CF₃, —CO₂R′, —CONR′₂, Ar—C₀₋₆alkyl orHet-C₀₋₆alkyl, wherein T is H, C₃₋₆cycloalkyl, Het or Ar, R² isCH₂CO₂R³; R³ is H, C₁₋₆alkyl, C₃₋₇cycloalkyl-C₀₋₄alkyl or Ar—C₀₋₄alkyl;R⁵ is W—(CR′₂)_(q)—Z—(CHR′)_(m), and R⁶ is H, C₁₋₆alkyl, Ar—C₀₋₆alkyl,Het-C₀₋₆alkyl, or C₃₋₆cycloalkyl-C₀₋₆alkyl, or R⁵ and R⁶ together form a5- or six-membered Het ring which is substituted by W, W is R⁹R″N—,R′R″NR′N—, R′R″NR′NCO—, R′₂NR′NC(═NR′)—, R′ONR′C(═NR′)—,

R′ is H, C₁₋₆alkyl, C₃₋₇cycloalkyl-C₀₋₄alkyl or Ar—C₀₋₄alkyl; R″ is R′,—C(O)R′ or —C(O)OR′″; R′″ is H, C₁₋₆alkyl or Ar—C₀₋₄alkyl; R⁷ is R′,—CF₃, —SR′, or —OR′; R⁸ is R′, C(O)R′, CN, NO₂, SO₂R′ or C(O)OR¹⁵; R⁹ isH, C₁₋₆alkyl, C₃₋₇cycloalkyl-C₀₋₄alkyl, Het-C₀₋₄alkyl or Ar—C₀₋₄alkyl; Xis N═CR′, C(O) or O; Y is absent, S or O; Z is (CH₂)_(t), Het, Ar orC₃₋₇cycloalkyl; q is 0 to 3; m is 0 to 2; and t is 0 to 2; which processcomprises: reacting a compound of formula (II):

wherein A¹ and R² are as defined above for formula (I); and R¹⁰ is Br,I, FSO₃—, ClSO₃— or CF₃SO₃−; with a Pd catalyst, carbon monoxide and anamine of the formula (III)

wherein R⁵ and R⁶ are defined as above in formula (I) except that anybasic nitrogen group in R⁵ or R⁶ is protected, and thereafter removingany protecting groups.
 2. A process according to claim 1 wherein theamine of formula (III) is N′-benzyloxycarbonyl-4,4′-bipiperidine orN′-t-butyloxycarbonyl-4,4′-bipiperidine.
 3. A process according to claim1 wherein the palladium catalyst is (Ph₃P)₂Pd(Cl)₂.
 4. A processaccording to claim 1 which is conducted in a N-methylpyrrolidinonesolvent.
 5. A process according to claim 1 wherein R¹⁰ is I.
 6. Aprocess according to claim 1 wherein R¹⁰ is Br.
 7. A process accordingto claim 6 in which, greater than a 15 mole % of palladium catalyst isused.
 8. A process according to claim 6 in which greater than a 15 mole% of triphenyl phosphine is present.
 9. A process according to claim 8which is run in the presence of a reducing agent.
 10. A process forpreparing the intermediate compound of formula (II):

wherein R¹⁰ is Br, which comprises reacting a compound of formula (IV):

wherein A¹ and R² are as defined in claim 1, with N-bromosuccinimide anda tetraalkyl ammonium halide.
 11. A process for preparing theintermediate compound of formula (II):

wherein R¹⁰ is I, which comprises reacting a compound of formula (IV):

wherein A¹ and R² are as defined in claim 1, with ICl.pyridine in asolvent mixture of methylene dichloride and methanol.
 12. Anintermediate compound of the formula (II) or (IV):

wherein R¹⁰ is CF₃SO₃, Br or I, and A¹ and R² are as defined in claim 1.13. An intermediate compound of formula (IV):

wherein A¹ and R² are as defined in claim
 1. 14. A compound according toclaim 13 which is methyl(S)-2,3,4,5-tetrahydro-3-oxo-1H-1,4-benzodiazepine-2-acetate.
 15. Aprocess for preparing a compound according to claim 13, which comprises,reacting dimethyl N-[2-(cyano)phenyl]-aspartate with a reducing agent.16. A compound which is dimethyl N-[2-(cyano)phenyl]-aspartate.
 17. Aprocess for preparing compounds of formula (I):

wherein A¹ is NR¹ or CHR¹; R¹ is H, T—C₁₋₆alkyl, T—C₁₋₆oxoalkyl,T—C₂₋₆alkenyl, T—C₃₋₄oxoalkenyl, T—C₃₋₄oxoalkynyl, T—C₃₋₄alkynyl,C₃₋₆cycloalkyl, Ar or Het, optionally substituted by one or more ofhalo, —OR′, —CN, —NR′₂, —NO₂, —CF₃, —CO₂R′, —CONR′₂, Ar—C₀₋₆alkyl orHet-C₀₋₆alkyl, wherein T is H, C₃₋₆cycloalkyl, Het or Ar, R² isCH₂CO₂R³; R³ is H, C₁₋₆alkyl, C₃₋₇cycloalkyl-C₀₋₄alkyl or Ar—C₀₋₄alkyl;R⁵ is W-(CR′₂)_(q)-Z-(CHR′)_(m), and R⁶ is H, C₁₋₆alkyl, Ar—C₀₋₆alkyl,Het-C₀₋₆alkyl, or C₃₋₆cycloalkyl-C₀₋₆alkyl, or R⁵ and R⁶ together form a5- or six-membered Het ring which is substituted by W; W is R⁹R″N—,R′R″NR′N—, R′R″NR′NCO—, R′₂NR′NC(═NR′)—, R′ONR′C(═NR′)—,

R′ is H, C₁₋₆alkyl, C₃₋₇cycloalkyl-C₀₋₄alkyl or Ar—C₀₋₄alkyl; R″ is R′,—C(O)R′ or —C(O)OR′″; R′″ is H, C₁₋₆alkyl or Ar—C₀₋₄alkyl; R⁷ is R′,—CF₃, —SR′, or —OR′; R⁸ is R′, C(O)R′, CN, NO₂, SO₂R′ or C(O)OR¹⁵; R⁹ isH, C₁₋₆alkyl, C₃₋₇cycloalkyl-C₀₋₄alkyl, Het-C₀₋₄alkyl or Ar—C₀₋₄alkyl; Xis N═CR′, C(O) or O; Y is absent, S or O; Z is (CH₂)_(t), Het, Ar orC₃₋₇cycloalkyl; q is 0 to 3; m is 0 to 2; and t is 0 to 2; which processcomprises: converting a compound of formula (IV)

to a compound of formula (I).
 18. A process for preparing compounds offormula (I):

wherein A¹ is NR¹ or CHR¹; R¹ is H, T—C₁₋₆alkyl, T—C₁₋₆oxoalkyl,T—C₂₋₆alkenyl, T—C₃₋₄oxoalkenyl, T—C₃₋₄oxoalkynyl, T—C₃₋₄alkynyl,C₃₋₆cycloalkyl, Ar or Het, optionally substituted by one or more ofhalo, —OR′, —CN, —NR′₂, —NO₂, —CF₃, —CO₂R′, —CONR′₂, Ar—C₀₋₆alkyl orHet-C₀₋₆alkyl, wherein T is H, C₃₋₆cycloalkyl, Het or Ar, R² isCH₂CO₂R³; R³ is H, C₁₋₆alkyl, C₃₋₇cycloalkyl-C₀₋₄alkyl or Ar—C₀₋₄alkyl;R⁵ is W-(CR′₂)_(q)-Z-(CHR′)_(m), and R⁶ is H, C₁₋₆alkyl, Ar—C₀₋₆alkyl,Het-C₀₋₆alkyl, or C₃₋₆cycloalkyl-C₀₋₆alkyl, or R⁵ and R⁶ together form a5- or six-membered Het ring which is substituted by W; W is R⁹R″N—,R′R″NR′N—, R′R″NR′NCO—, R′₂NR′NC(═NR′)—, R′ONR′C(═NR′)—,

R′ is H, C₁₋₆alkyl, C₃₋₇cycloalkyl-C₀₋₄alkyl or Ar—C₀₋₄alkyl; R″ is R′,—C(O)R′ or —C(O)OR′″; R′″ is H, C₁₋₆alkyl or Ar—C₀₋₄alkyl; R⁷ is R′,—CF₃, —SR′, or —OR′; R⁸ is R′, C(O)R′, CN, NO₂, SO₂R′ or C(O)OR¹⁵; R⁹ isH, C₁₋₆alkyl, C₃₋₇cycloalkyl-C₀₋₄alkyl, Het-C₀₋₄alkyl or Ar—C₀₋₄alkyl; Xis N═CR′, C(O) or O; Y is absent, S or O; Z is (CH₂)_(t), Het, Ar orC₃₋₇cycloalkyl; q is 0 to 3; m is 0 to 2; and t is 0 to 2; which processcomprises: converting dimethyl N-[2-(cyano)phenyl]-asparte to a compoundof formula (I).
 19. A process according to claim 1 wherein R¹ is methyl.20. A process according to claim 17 wherein R³ is methyl, t-butyl orbenzyl.
 21. A process according to claim 1 wherein the amine of formula(III) is 4,4′-bipiperidine.
 22. A compound of claim 13 in which A¹equals NCH₃, and R² equals —CH₂CO₂Me.